tbuckley/cabot-search huggingface dataset:
Cediranib in Combination with Olaparib in Patients without a Germline BRCA1/2 Mutation and with Recurrent Platinum-Resistant Ovarian Cancer: Phase IIb CONCERTO Trial
Authors: Jung-Min Lee, Richard G. Moore, Sharad Ghamande, Min S. Park, John P. Diaz, Julia Chapman, James Kendrick, Brian M. Slomovitz, Krishnansu S. Tewari, Elizabeth S. Lowe, Tsveta Milenkova, Sanjeev Kumar, Mike Dymond, Jessica Brown, Joyce F. Liu
Journal: Clinical Cancer Research (2022)

Abstract Purpose: The efficacy, safety, and tolerability of cediranib plus olaparib (cedi/ola) were investigated in patients with nongermline–BRCA-mutated (non-gBRCAm) platinum-resistant recurrent ovarian cancer. Patients and Methods: PARP inhibitor–naïve women aged ≥18 years with platinum-resistant non-gBRCAm ovarian cancer, ECOG performance status of 0–2, and ≥3 prior lines of therapy received cediranib 30 mg once daily plus olaparib 200 mg twice daily in this single-arm, multicenter, phase IIb trial. The primary endpoint was objective response rate (ORR) by independent central review (ICR) using RECIST 1.1. Progression-free survival (PFS), overall survival (OS), and safety and tolerability were also examined. Results: Sixty patients received cedi/ola, all of whom had confirmed non-gBRCAm status. Patients had received a median of four lines of chemotherapy; most (88.3%) had received prior bevacizumab. ORR by ICR was 15.3%, median PFS was 5.1 months, and median OS was 13.2 months. Forty-four (73.3%) patients reported a grade ≥3 adverse event (AE), with one patient experiencing a grade 5 AE (sepsis), considered unrelated to the study treatment. Dose interruptions, reductions, and discontinuations due to AEs occurred in 55.0%, 18.3%, and 18.3% of patients, respectively. Patients with high global loss of heterozygosity (gLOH) had ORR of 26.7% [4/15; 95% confidence interval (CI), 7.8–55.1], while ORR was 12.5% (4/32; 95% CI, 3.5–29.0) in the low gLOH group. Conclusions: Clinical activity was shown for the cedi/ola combination in heavily pretreated, non-gBRCAm, platinum-resistant patients with ovarian cancer despite failing to meet the target ORR of 20%, highlighting a need for further biomarker studies.
Sex differences among patients with transthyretin amyloid cardiomyopathy – from diagnosis to prognosis
Authors: Rishi K. Patel, Adam Ioannou, Yousuf Razvi, Liza Chacko, Lucia Venneri, Francesco Bandera, Daniel Knight, Tushar Kotecha, Ana Martinez‐Naharro, Ambra Masi, Aldostefano Porcari, James Brown, Kiara Patel, Charlotte Manisty, James Moon, Dorota Rowczenio, Janet A. Gilbertson, Gianfranco Sinagra, Helen Lachmann, Ashutosh Wechalekar, Aviva Petrie, Carol Whelan, Philip N. Hawkins, Julian D. Gillmore, Marianna Fontana
Journal: European Journal of Heart Failure (2022)
Health service planning to assess the expected impact of centralising specialist cancer services on travel times, equity, and outcomes: a national population-based modelling study
Authors: Ajay Aggarwal, Lu Han, Stephanie van der Geest, Daniel Lewis, Yolande Lievens, Josep Borras, David Jayne, Richard Sullivan, Marco Varkevisser, Jan van der Meulen
Journal: The Lancet Oncology (2022)
BET inhibition triggers antitumor immunity by enhancing MHC class I expression in head and neck squamous cell carcinoma
Authors: Ming Zhang, Ganping Wang, Zhikun Ma, Gan Xiong, Wenjin Wang, Zhengxian Huang, Yuehan Wan, Xiuyun Xu, Rosalie G. Hoyle, Chen Yi, Jinsong Hou, Xiqiang Liu, Demeng Chen, Jiong Li, Cheng Wang
Journal: Molecular Therapy (2022)

BET inhibition has been shown to have a promising antitumor effect in multiple tumors. However, the impact of BET inhibition on antitumor immunity was still not well documented in HNSCC. In this study, we aim to assess the functional role of BET inhibition in antitumor immunity and clarify its mechanism. We show that BRD4 is highly expressed in HNSCC and inversely correlated with the infiltration of CD8+ T cells. BET inhibition potentiates CD8+ T cell-based antitumor immunity in vitro and in vivo. Mechanistically, BRD4 acts as a transcriptional suppressor and represses the expression of MHC class I molecules by recruiting G9a. Pharmacological inhibition or genetic depletion of BRD4 potently increases the expression of MHC class I molecules in the absence and presence of IFN-γ. Moreover, compared to PD-1 blocking antibody treatment or JQ1 treatment individually, the combination of BET inhibition with anti-PD-1 antibody treatment significantly enhances the antitumor response in HNSCC. Taken together, our data unveil a novel mechanism by which BET inhibition potentiates antitumor immunity via promoting the expression of MHC class I molecules and provides a rationale for the combination of ICBs with BET inhibitors for HNSCC treatment.
CD24-Siglec axis is an innate immune checkpoint against metaflammation and metabolic disorder
Authors: Xu Wang, Mingyue Liu, Jifeng Zhang, Nicholas K. Brown, Peng Zhang, Yan Zhang, Heng Liu, Xuexiang Du, Wei Wu, Martin Devenport, Weng Tao, Yang Mao-Draayer, Guo-Yun Chen, Y. Eugene Chen, Pan Zheng, Yang Liu
Journal: Cell Metabolism (2022)

The molecular interactions that regulate chronic inflammation underlying metabolic disease remain largely unknown. Since the CD24-Siglec interaction regulates inflammatory response to danger-associated molecular patterns (DAMPs), we have generated multiple mouse strains with single or combined mutations of Cd24 or Siglec genes to explore the role of the CD24-Siglec interaction in metaflammation and metabolic disorder. Here, we report that the CD24-Siglec-E axis, but not other Siglecs, is a key suppressor of obesity-related metabolic dysfunction. Inactivation of the CD24-Siglec-E pathway exacerbates, while CD24Fc treatment alleviates, diet-induced metabolic disorders, including obesity, dyslipidemia, insulin resistance, and nonalcoholic steatohepatitis (NASH). Mechanistically, sialylation-dependent recognition of CD24 by Siglec-E induces SHP-1 recruitment and represses metaflammation to protect against metabolic syndrome. A first-in-human study of CD24Fc (NCT02650895) supports the significance of this pathway in human lipid metabolism and inflammation. These findings identify the CD24-Siglec-E axis as an innate immune checkpoint against metaflammation and metabolic disorder and suggest a promising therapeutic target for metabolic disease.
Concerns about the use of polygenic embryo screening for psychiatric and cognitive traits
Authors: Todd Lencz, Maya Sabatello, Anna Docherty, Roseann E Peterson, Takahiro Soda, Jehannine Austin, Laura Bierut, David Crepaz-Keay, David Curtis, Franziska Degenhardt, Laura Huckins, Gabriel Lazaro-Munoz, Manuel Mattheisen, Bettina Meiser, Holly Peay, Marcella Rietschel, Consuelo Walss-Bass, Lea K Davis
Journal: The Lancet Psychiatry (2022)
Prognostic Stratification of Multiple Myeloma Using Clinicogenomic Models: Validation and Performance Analysis of the IAC-50 Model
Authors: Adrián Mosquera Orgueira, Marta Sonia González Pérez, José Ángel Díaz Arias, Beatriz Antelo Rodríguez, María-Victoria Mateos
Journal: HemaSphere (2022)

A growing need to evaluate risk-adapted treatments in multiple myeloma (MM) exists. Several clinical and molecular scores have been developed in the last decades, which individually explain some of the variability in the heterogeneous clinical behavior of this neoplasm. Recently, we presented Iacobus-50 (IAC-50), which is a machine learning-based survival model based on clinical, biochemical, and genomic data capable of risk-stratifying newly diagnosed MM patients and predicting the optimal upfront treatment scheme. In the present study, we evaluated the prognostic value of the IAC-50 gene expression signature in an external cohort composed of patients from the Total Therapy trials 3, 4, and 5. The prognostic value of IAC-50 was validated, and additionally we observed a better performance in terms of progression-free survival and overall survival prediction compared with the UAMS70 gene expression signature. The combination of the IAC-50 gene expression signature with traditional prognostic variables (International Staging System [ISS] score, baseline B2-microglobulin, and age) improved the performance well above the predictability of the ISS score. IAC-50 emerges as a powerful risk stratification model which might be considered for risk stratification in newly diagnosed myeloma patients, in the context of clinical trials but also in real life.
Gut microbiota-derived metabolites confer protection against SARS-CoV-2 infection
Authors: Julia A. Brown, Katherine Z. Sanidad, Serena Lucotti, Carolin M. Lieber, Robert M. Cox, Aparna Ananthanarayanan, Srijani Basu, Justin Chen, Mengrou Shan, Mohammed Amir, Fabian Schmidt, Yiska Weisblum, Michele Cioffi, Tingting Li, Florencia Madorsky Rowdo, M. Laura Martin, Chun-Jun Guo, Costas A. Lyssiotis, Brian T. Layden, Andrew J. Dannenberg, Paul D. Bieniasz, Benhur Lee, Naohiro Inohara, Irina Matei, Richard K. Plemper, Melody Y. Zeng
Journal: Gut Microbes (2022)

The gut microbiome is intricately coupled with immune regulation and metabolism, but its role in Coronavirus Disease 2019 (COVID-19) is not fully understood. Severe and fatal COVID-19 is characterized by poor anti-viral immunity and hypercoagulation, particularly in males. Here, we define multiple pathways by which the gut microbiome protects mammalian hosts from SARS-CoV-2 intranasal infection, both locally and systemically, via production of short-chain fatty acids (SCFAs). SCFAs reduced viral burdens in the airways and intestines by downregulating the SARS-CoV-2 entry receptor, angiotensin-converting enzyme 2 (ACE2), and enhancing adaptive immunity via GPR41 and 43 in male animals. We further identify a novel role for the gut microbiome in regulating systemic coagulation response by limiting megakaryocyte proliferation and platelet turnover via the Sh2b3-Mpl axis. Taken together, our findings have unraveled novel functions of SCFAs and fiber-fermenting gut bacteria to dampen viral entry and hypercoagulation and promote adaptive antiviral immunity.
Prevalence of Diabetic Retinopathy in Indigenous and Non-Indigenous Australians
Authors: Mark A. Chia, Joshua R. Taylor, Kelsey V. Stuart, Anthony P. Khawaja, Paul J. Foster, Pearse A. Keane, Angus W. Turner
Journal: Ophthalmology (2022)

This systematic review and meta-analysis summarizes evidence relating to the prevalence of diabetic retinopathy (DR) among Indigenous and non-Indigenous Australians.Indigenous Australians suffer disproportionately from diabetes-related complications. Exploring ethnic variation in disease is important for equitable distribution of resources and may lead to identification of ethnic-specific modifiable risk factors. Existing DR prevalence studies comparing Indigenous and non-Indigenous Australians have shown conflicting results.This study was conducted following Joanna Briggs Institute guidance on systematic reviews of prevalence studies (PROSPERO ID: CRD42022259048). We performed searches of Medline (Ovid), EMBASE, and Web of Science until October 2021, using a strategy designed by an information specialist. We included studies reporting DR prevalence among diabetic patients in Indigenous and non-Indigenous Australian populations. Two independent reviewers performed quality assessments using a 9-item appraisal tool. Meta-analysis and meta-regression were performed using double arcsine transformation and a random-effects model comparing Indigenous and non-Indigenous subgroups.Fifteen studies with 8219 participants met criteria for inclusion. The Indigenous subgroup scored lower on the appraisal tool than the non-Indigenous subgroup (mean score 50% vs. 72%, P = 0.04). In the unadjusted meta-analysis, DR prevalence in the Indigenous subgroup (30.2%; 95% confidence interval [CI], 24.9-35.7) did not differ significantly (P = 0.17) from the non-Indigenous subgroup (23.7%; 95% CI, 16.8-31.4). After adjusting for age and quality, DR prevalence was higher in the Indigenous subgroup (P < 0.01), with prevalence ratio point estimates ranging from 1.72 to 2.58, depending on the meta-regression model. For the secondary outcomes, prevalence estimates were higher in the Indigenous subgroup for diabetic macular edema (DME) (8.7% vs. 2.7%, P = 0.02) and vision-threatening DR (VTDR) (8.6% vs. 3.0%, P = 0.03) but not for proliferative DR (2.5% vs. 0.8%, P = 0.07).Indigenous studies scored lower for methodological quality, raising the possibility that systematic differences in research practices may be leading to underestimation of disease burden. After adjusting for age and quality, we found a higher DR prevalence in the Indigenous subgroup. This contrasts with a previous review that reported the opposite finding of lower DR prevalence using unadjusted pooled estimates. Future epidemiological work exploring DR burden in Indigenous communities should aim to address methodological weaknesses identified by this review.
Persistent DNA damage underlies tubular cell polyploidization and progression to chronic kidney disease in kidneys deficient in the DNA repair protein FAN1
Authors: Merlin Airik, Yu Leng Phua, Amy B. Huynh, Blake T. McCourt, Brittney M. Rush, Roderick J. Tan, Jerry Vockley, Susan L. Murray, Anthony Dorman, Peter J. Conlon, Rannar Airik
Journal: Kidney International (2022)
Dysregulated FOXM1 signaling in the regulation of cancer stem cells
Authors: Gulab Sher, Tariq Masoodi, Kalyani Patil, Sabah Akhtar, Shilpa Kuttikrishnan, Aamir Ahmad, Shahab Uddin
Journal: Seminars in Cancer Biology (2022)

Since the introduction of the cancer stem cell (CSC) paradigm, significant advances have been made in understanding the functional and biological plasticity of these elusive components in malignancies. Endowed with self-renewing abilities and multilineage differentiation potential, CSCs have emerged as cellular drivers of virtually all facets of tumor biology, including metastasis, tumor recurrence/relapse, and drug resistance. The functional and biological characteristics of CSCs, such as self-renewal, cell fate decisions, survival, proliferation, and differentiation are regulated by an array of extracellular factors, signaling pathways, and pluripotent transcriptional factors. Besides the well-characterized regulatory role of transcription factors OCT4, SOX2, NANOG, KLF4, and MYC in CSCs, evidence for the central role of Forkhead box transcription factor FOXM1 in the establishment, maintenance, and functions of CSCs is accumulating. Conventionally identified as a master regulator of the cell cycle, a comprehensive understanding of this molecule has revealed its multifarious oncogenic potential and uncovered its role in angiogenesis, invasion, migration, self-renewal, and drug resistance. This review compiles the large body of literature that has accumulated in recent years that provides evidence for the mechanisms by which FOXM1 expression promotes stemness in glioblastoma, breast, colon, ovarian, lung, hepatic, and pancreatic carcinomas. We have also compiled the data showing the association of stem cell mediators with FOXM1 using TCGA mRNA expression data. Further, the prognostic importance of FOXM1 and other stem cell markers is presented. The delineation of FOXM1-mediated regulation of CSCs can aid in the development of molecularly targeted pharmacological approaches directed at the selective eradication of CSCs in several human malignancies.
Discovery of novel heteroaryl alkynes for highly potent KITD816V cells inhibition to treat gastrointestinal stromal tumors
Authors: Zhicheng Xie, Lin Li, Yihao Guo, Mi Zhang, Taiwen Chen, Yongpeng Li, Xin Li, Xi Zhu, Yu Zhang, Liguang Lou, Youhong Hu
Journal: Acta Pharmaceutica Sinica B (2022)
Effectiveness of MRNA booster vaccine among healthcare workers in New York City during the Omicron surge, December 2021 to January 2022
Authors: Elizabeth V. Robilotti, Karissa Whiting, Anabella Lucca, Chester Poon, Krupa Jani, Tracy McMillen, Scott Freeswick, Deborah Korenstein, N. Esther Babady, Venkatraman E. Seshan, Mini Kamboj
Journal: Clinical Microbiology and Infection (2022)
A near-infrared AIE probe and its applications for specific in vitro and in vivo two-photon imaging of lipid droplets
Authors: Hui-Fang Su, Qiu-Chen Peng, Yong U Liu, Tao Xie, Pei-Pei Liu, Yu-Chen Cai, Wei Wen, Yi-Hong Yu, Kai Li, Shuang-Quan Zang
Journal: Biomaterials (2022)
Aberrant iron distribution via hepatocyte-stellate cell axis drives liver lipogenesis and fibrosis
Authors: Hong Gao, Zhongmou Jin, Gautam Bandyopadhyay, Gaowei Wang, Dinghong Zhang, Karina Cunha e Rocha, Xiao Liu, Huayi Zhao, Tatiana Kisseleva, David A. Brenner, Michael Karin, Wei Ying
Journal: Cell Metabolism (2022)
A boronate-based modular assembly nanosystem to block the undesirable crosstalk between hepatic stellate cells and Kupffer cells
Authors: Huizhen Jia, Ling Ding, Ao Yu, Weimin Tang, Siyuan Tang, Chuhan Zhang, David Oupický
Journal: Bioactive Materials (2022)

Crosstalk between Kupffer cells (KCs) and hepatic stellate cells (HSCs) plays an important role in multiple liver disease conditions, including the formation of liver fibrosis in alcohol-associated liver disease (AALD). Therapeutic targeting of the KC-HSC crosstalk is a prime target for therapeutic interventions. Herein, a novel modular nanosystem was designed and prepared through the self-assembly utilizing boric acid and catechol interactions to prepare polymers modified with a CXCR4-inhibiting moieties. The polymers were used to encapsulate anti-miR-155 and to block the undesirable crosstalk between HSCs and KCs by downregulating miR-155 expression in KCs with the parallel inhibition of CXCR4 signaling in activated HSCs. The combined inhibition of miR-155 and CXCR4 at two different liver cell types achieved improved antifibrosis effects in a mouse model of AALD fibrosis. Our finding highlights the key role that blocking the undesirable crosstalk between HSCs and KCs plays in reversing AALD fibrosis as well as demonstrates a proof-of-concept approach for designing and constructing multifunctional delivery nanosystems using orthogonal functional modules based on the understanding of disease mechanisms.
Wet-suction versus slow-pull technique for endoscopic ultrasound-guided fine-needle biopsy: a multicenter, randomized, crossover trial
Authors: Stefano Francesco Crinò, Maria Cristina Conti Bellocchi, Roberto Di Mitri, Frediano Inzani, Mihai Rimbaș, Andrea Lisotti, Guido Manfredi, Anthony Y. B. Teoh, Benedetto Mangiavillano, Oriol Sendino, Laura Bernardoni, Erminia Manfrin, Daniela Scimeca, Elettra Unti, Angela Carlino, Theodor Voiosu, R. Bogdan Mateescu, Pietro Fusaroli, Stefania Lega, Elisabetta Buscarini, Lorena Pergola, Shannon M. Chan, Laura Lamonaca, Àngels Ginès, Gloria Fernández-Esparrach, Antonio Facciorusso, Alberto Larghi
Journal: Endoscopy (2022)

Background It is unknown whether there is an advantage to using the wet-suction or slow-pull technique during endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) with new-generation needles. We aimed to compare the performance of each technique in EUS-FNB. Methods This was a multicenter, randomized, single-blind, crossover trial including patients with solid lesions of ≥ 1 cm. Four needle passes with 22 G fork-tip or Franseen-type needles were performed, alternating the wet-suction and slow-pull techniques in a randomized order. The primary outcome was the histological yield (samples containing an intact piece of tissue of at least 550 μm). Secondary end points were sample quality (tissue integrity and blood contamination), diagnostic accuracy, and adequate tumor fraction. Results Overall, 210 patients with 146 pancreatic and 64 nonpancreatic lesions were analyzed. A tissue core was retrieved in 150 (71.4 %) and 129 (61.4 %) cases using the wet-suction and the slow-pull techniques, respectively (P = 0.03). The mean tissue integrity score was higher using wet suction (P = 0.02), as was the blood contamination of samples (P &lt; 0.001). In the two subgroups of pancreatic and nonpancreatic lesions, tissue core rate and tissue integrity score were not statistically different using the two techniques, but blood contamination was higher with wet suction. Diagnostic accuracy and tumor fraction did not differ between the two techniques. Conclusion Overall, the wet-suction technique in EUS-FNB resulted in a higher tissue core procurement rate compared with the slow-pull method. Diagnostic accuracy and the rate of samples with adequate tumor fraction were similar between the two techniques.
Assessment and Optimization of Explainable Machine Learning Models Applied to Transcriptomic Data
Authors: Yongbing Zhao, Jinfeng Shao, Yan W. Asmann
Journal: Genomics Proteomics & Bioinformatics (2022)

Abstract Explainable artificial intelligence aims to interpret how machine learning models make decisions, and many model explainers have been developed in the computer vision field. However, understanding of the applicability of these model explainers to biological data is still lacking. In this study, we comprehensively evaluated multiple explainers by interpreting pre-trained models for predicting tissue types from transcriptomic data and by identifying the top contributing genes from each sample with the greatest impacts on model prediction. To improve the reproducibility and interpretability of results generated by model explainers, we proposed a series of optimization strategies for each explainer on two different model architectures of multilayer perceptron (MLP) and convolutional neural network (CNN). We observed three groups of explainer and model architecture combinations with high reproducibility. Group II, which contains three model explainers on aggregated MLP models, identified top contributing genes in different tissues that exhibited tissue-specific manifestation and were potential cancer biomarkers. In summary, our work provides novel insights and guidance for exploring biological mechanisms using explainable machine learning models.
Cancer: slaying the nine-headed Hydra
Authors: J.J. Adashek, V. Subbiah, C.B. Westphalen, A. Naing, S. Kato, R. Kurzrock
Journal: Annals of Oncology (2022)

Modern medicine continues to evolve, and the treatment armamentarium for various diseases grows more individualized across a breadth of medical disciplines. Cure rates for infectious diseases that were previously pan-fatal approach 100% because of the identification of the specific pathogen(s) involved and the use of appropriate combinations of drugs, where needed, to completely extinguish infection and hence prevent emergence of resistant strains. Similarly, with the assistance of technologies such as next-generation sequencing and immunomic analysis as part of the contemporary oncology armory, therapies can be tailored to each tumor. Importantly, molecular interrogation has revealed that metastatic cancers are distinct from each other and complex. Therefore, it is conceivable that rational personalized drug combinations will be needed to eradicate cancers, and eradication will be necessary to mitigate clonal evolution and resistance.
Monkeypox virus isolation from a semen sample collected in the early phase of infection in a patient with prolonged seminal viral shedding
Authors: Daniele Lapa, Fabrizio Carletti, Valentina Mazzotta, Giulia Matusali, Carmela Pinnetti, Silvia Meschi, Roberta Gagliardini, Francesca Colavita, Annalisa Mondi, Claudia Minosse, Laura Scorzolini, Stefania Cicalini, Gaetano Maffongelli, Eliana Specchiarello, Marta Camici, Aurora Bettini, Francesco Baldini, Massimo Francalancia, Klizia Mizzoni, Anna Rosa Garbuglia, Emanuele Nicastri, Enrico Girardi, Andrea Antinori, Francesco Vaia, Fabrizio Maggi
Journal: The Lancet Infectious Diseases (2022)